Duchenne Muscular Dystrophy (DMD) is a lethal muscle wasting disease caused by the lack of dystrophin, which eventually leads to apoptosis of muscle cells and impaired muscle contractility. Induced pluripotent stem cells (iPSC) offer the potential to correct the DMD gene defect and create healthy cells for transplantation without causing immune activation. However, this requires engineering iPSCs to facilitate homing and engraftment into diseased muscle tissue without promoting tumorigenesis. Our long-term goal is to optimize the differentiation of iPSC into myogenic progenitor cells (MPC) that are directed to home into muscle tissue and engraft without undergoing unrestrained growth. Our central hypothesis is that precise MPC genetic engineering, coupled with targeted modification of the host muscle niche by preconditioning or exosome delivery, will boost homing and engraftment of donor iPSC-derived MPC via the SDF-CXCR4 axis to safely and effectively treat DMD. The rationale is to develop methodology to produce large quantities of functional MPC from patients with DMD that are tumor free and can effectively home to sites of muscle injury and facilitate repair. We plan to test our central hypothesis and accomplish the objectives of this application by pursuing the following three specific aims. In Aim 1, we will test the hypothesis that iPSC-derived progenitor cells are effective and safe for regeneration of dystrophic muscle. In Aim 2, we will test the hypothesis that activation of CXCR4 in iPSC-derived myogenic precursors from DMD mice using a CRISPR-on based genomic platform improves engraftment of donor cells in DMD mice. In Aim 3, we will test the hypothesis that optimizing the regenerative microenvironment in muscle by ischemic preconditioning or iPSC-exosome-mediated delivery of SDF-1? protein enhances the homing and/or survival of donor MPC to augment muscle repair. These experiments have the potential to demonstrate that transplantation of iPSC-derived progenitors, coupled with methods to optimize the host muscle microenvironment, will more effectively ameliorate dystrophic pathology and improve the quality of life for patients with DMD.